The overall objective of these studies is to clearly define the role of dietary fat (fatty acids) in the regulation of plasma lipoproteins and platelet sensitivity to aggregation, i.e., the two key elements initiating atherogenesis. Although saturated fatty acids are known to be the major dietary factor causing elevation in the plasma cholesterol concentration, the specific contribution of each saturated fatty acid is controversial. Furthermore, our preliminary studies suggest that the contribution of each fatty acid varies depending on the balance of other fatty acids present. How this interplay of fatty acids affects platelet aggregation is only superficially explored to date. To address these issues we have established three specific aims that will be applied in experimental model systems including whole animals (gerbils, monkeys) and tissue culture (hepatocytes). First, gerbils and monkeys will be fed various blends of fats to determine the impact of specific fatty acids on lipoprotein (LDL, HDL) kinetics, including cholesteryl ester transfer activity between lipoproteins. Second, this regulatory control by fatty acids will be further documented in a tightly controlled in vitro system with cultured hepatocytes during incubation with lipoproteins from monkeys or gerbils fed specific fat blends or with albumin-bound fatty acids, either as single fatty acids or blends of fatty acids that mimic those in the diet. The third aim will establish the effect of dietary fatty acids on platelets exposed to collagen ex vivo. By manipulating the source of platelets and plasma in cross-over experiments, we will separate the individual impact of platelet membrane fatty acid changes (affecting eicosanoid metabolism) from plasma lipoprotein-induced modulation of platelet aggregation (LDL/HDL) as influenced by the fatty acids consumed. In the final analysis we would suggest that these carefully designed experiments in highly selective models will provide the most in-depth scrutiny of the dietary (fatty acid) impact on lipoprotein metabolism and platelet aggregation ever undertaken in well-controlled nutritionally- defined experiments.